Vascular closure devices and methods providing hemostatic enhancement

ABSTRACT

Drug eluting vascular closure devices and methods for closing a blood vessel puncture site disposed at a distal end of a tissue tract are described. The devices and methods rely on a combination of the body&#39;s own natural mechanism to achieve hemostasis with chemical and/or biological agents to accelerate the hemostatic process. One method includes the steps of introducing a closure device through the tissue tract and deploying an expansible member at a distal end of the device within the blood vessel to occlude the puncture site. A chemical and/or biological sealing member disposed proximal the expansible member is then displaced so as to expose a chemical and/or biological region or release region of the device. At least one chemical and/or biological agent is thereafter released from the device and into the tissue tract to accelerate the occlusion process in the tract.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application is a continuation-in-part of U.S. patentapplication Ser. No. 11/302,951 (Attorney Docket No. 021872-002200US),filed on Dec. 13, 2005, the full disclosure of which is incorporatedherein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to devices and methods forpercutaneous sealing of puncture sites in body lumens or tissue tracts.More specifically, the present invention relates to drug elutingvascular closure devices and methods for hemostasis of vascular puncturesites.

Percutaneous access of blood vessels in the human body is routinelyperformed for diagnostics or interventional procedures such as coronaryand peripheral angiography, angioplasty, atherectomies, placement ofvascular stents, coronary retroperfusion and retroinfusion, cerebralangiograms, treatment of strokes, cerebral aneurysms, and the like.Patients undergoing these procedures are often treated withanti-coagulants such as heparin, thrombolytics, and the like, which makethe closure and hemostasis process of the puncture site in the vesselwall at the completion of such interventional procedures more difficultto achieve.

Various devices have been introduced to provide hemostasis, however nonehave been entirely successful. Some devices utilize collagen or otherbiological plugs to seal the puncture site. Alternatively, suturesand/or staples have also been applied to close the puncture site.External foreign objects such as plugs, sutures, or staples however maycause tissue reaction, inflammation, and/or infection as they all “leavesomething behind” to achieve hemostasis.

There is also another class of devices that use the body's own naturalmechanism to achieve hemostasis wherein no foreign objects are leftbehind. Such devices typically provide hemostasis by sealing thepuncture site from the inside of the vessel wall wherein the device isleft in place in the vessel lumen until hemostasis is reached andthereafter removed. Although such safe and simple devices have achievedrelative levels of success, they often can be slow in achieving completehemostasis, particularly in highly anti-coagulated patients. Ofparticular interest to the present invention, examples of such devicesare described in co-pending, commonly owned application Ser. No.10/795,019 (Attorney Docket No. 021872-001810US) filed on Mar. 3, 2004;Ser. No. 10/821,633 (Attorney Docket No. 0217872-001900US), filed onApr. 9, 2004; Ser. No. 10/857,177 (Attorney Docket No. 021872-002000US),filed on May 27, 2004; and Ser. No. 10/974,008 (Attorney Docket No.021872-002010US), filed on Oct. 25, 2004, the full disclosures of whichare incorporated herein by reference.

There is yet another class of devices where highly thrombogenicsubstances are mixed and injected to the puncture site for the purposeof accelerating the hemostatic process. These mixtures contain one ormore clot promoting substances, such as thrombin and/or fibrinogen,along with other substances, such as collagen. These devices generallywork by first occluding the puncture site from the inside of the vessel,usually by use of a balloon, and then injecting the mixture into thetissue tract. The balloon is then removed. Such devices suffer fromseveral drawbacks which may cause severe complications. For example, theoccluding member may not be adequate to prevent these highlythrombogenic substances from entering the blood vessel. Further, theinjection of the mixture is often not well controlled and highlytechnique dependant, which again may allow these substances to enter theblood stream.

In light of the above, it would be desirable to provide alternativedevices and methods for providing complete hemostasis of a puncture sitein a body lumen, particularly blood vessels of the human body. It wouldbe particularly desirable if such devices and methods utilize the body'sown natural healing mechanism to achieve hemostasis. It would be furtherdesirable if the natural hemostatic process can be safely accelerated bythe controlled use of chemical and/or biological agents. It would befurther desirable if such devices and systems utilize a simpleconstruction and user interface allowing for convenient applicationwithout numerous intermediary steps. Further, such devices should besafe and reliable without the need for much user intervention. At leastsome of these objective will be met by the devices and methods of thepresent invention described hereinafter.

2. Description of the Background Art

Hemostasis devices for use in blood vessels and tracts in the body aredescribed in pending U.S. patent application Ser. Nos. 10/974,008;10/857,177; 10/821,633; 10/795,019; and 10/718,504 and U.S. Pat. Nos.6,656,207; 6,464,712; 6,056,770; 6,056,769; 6,045,570; 6,022,361;5,951,589; 5,922,009; and 5,782, 860, assigned to the assignee of thepresent application. The following U.S. Patents and Publications may berelevant to the present invention: U.S. Pat. Nos. 4,744,364; 4,852,568;4,890,612; 5,108,421; 5,171,259; 5,258,000; 5,383,896; 5,419,765;5,454,833; 5,626,601; 5,630,833; 5,634,936; 5,728,134; 5,836,913;5,861,003; 5,868,778; 5,951,583; 5,957,952; 6,017,359; 6,048,358; and6,296,657; U.S. Publication Nos. 2002/0133123; 2003/0055454;2003/0045835; and 2004/0243052. The full disclosures of each of theabove mentioned references are incorporated herein by reference.

BRIEF SUMMARY OF THE INVENTION

The present invention provides closure devices and methods forpercutaneous access and closure of puncture sites in a body lumen,particularly femoral arteries and other blood vessels of the human body.It will be appreciated however that application of the present inventionis not limited to the blood vasculature, and as such may be applied toany of the vessels, even severely tortuous vessels, ducts, and cavitiesfound in the body as well as tissue tracts. Such closure devices andmethods utilize the body's own natural healing mechanism to achievehemostasis.

In particular, the present invention provides methods and devices forclosing and sealing luminal punctures by providing physical occlusion ofthe puncture site together with chemical or biological promotion ofhemostasis activity proximal of the occlusion. Methods for closing ablood vessel or other luminal puncture site located at a distal end of atissue tract comprise introducing a closure device through the tissuetract. An expansible member is then deployed from the device within theblood vessel or other body lumen in order to occlude the puncture site.Blood within the vessel wall puncture and the tissue tract proximal tothe puncture is exposed to a chemical and/or biological agent carried bythe device. The chemical and/or biological agent is selected to promotehemostasis within the tissue tract. After sufficient hemostasis andclosure has been achieved, the expansible member will be collapsed andthe device removed from the tissue tract, thus eliminating orsignificantly reducing the need to apply external pressure to maintainhemostasis and promote healing.

In one exemplary embodiment, the chemical and/or biological agent isimmobilized on the device, typically in a region immediately proximal tothe expansible member, and is exposed by displacing a sealing memberwhich initially covers the chemical and/or biological agent. Typically,the sealing member is a tubular sheath or other member which covers thechemical and/or biological agent as the device is introduced through thetissue tract and which may be axially retracted after the expansiblemember has been deployed within the blood vessel or other body lumen. Itwill be appreciated, however, that the sealing member could comprise awide variety of other configurations, including a rotatable component, atear-away component, a biodegradable component which dissolves uponexposure to blood or other body fluids, or the like.

The immobilized chemical and/or biological agent may be either solubleor insoluble. Soluble chemical and/or biological agents will be selectedso that at least a portion thereof will dissolve and be released intothe blood after the agent has been exposed to the tissue tract.Exemplary soluble chemical and/or biological agents are selected fromthe group consisting of thrombin (a pro-coagulant), epinephrine (avasoconstrictor), watersoluble chitosan (a platelet aggregator), and thelike.

Insoluble immobilized chemical and/or biological agents will typicallyhave a catalytic or physical activity which promotes hemostasis. Forexample, the insoluble chemical and/or biological agents may have anegative electrical charge which promotes coagulation. Exemplarychemical and/or biological agents having such a negative charge includekaolin and silica. Alternatively, the insoluble chemical and/orbiological agents may have a positive electrical charge which attractsplatelets to promote clotting. Exemplary insoluble chemical and/orbiological agents having a positive charge include chitosan. Stillfurther, the insoluble chemical and/or biological agents may inhibit theactivity of heparin in order to reduce the inhibition of clotting inheparinized patients. Exemplary heparin-inhibitors include protaminesulfate.

Instead exposing an immobilized chemical and/or biological agent, themethods of the present invention may comprise injecting or otherwisedelivering the chemical and/or biological agent into the tissue tract inthe region proximal to the deployed expansible member. Such injectionwill typically be through an injection lumen provided within the devicebut could also be through a separate lumen or device. Exemplaryinjectible chemical and/or biological agents include thrombin,epinephrine, protamine sulfate, suspensions of insoluble kaolin, silica,or chitosan, and the like.

Devices according to the present invention will comprise a shaft havinga proximal end, a distal end, and an expansible member located near thedistal end on the shaft. The shaft will be configured to be advancedthrough the tissue tract in order to locate the expansible memberthrough the blood vessel or other luminal puncture site so that theexpansible member may be expanded within the lumen. A sealing member isretractably disposed over at least a portion of the shaft proximal tothe expansible member, and a chemical and/or biological agent selectedto promote hemostasis is disposed beneath the sealing member so that atleast a portion of the agent may be exposed by retracing or otherwisemoving the sealing member. The chemical and/or biological agents aretypically immobilized on the shaft, and exemplary immobilized agentshave been described above in connection with the methods of the presentinvention.

In a first embodiment, a device for closing a blood vessel puncture sitedisposed at a distal end of a tissue tract comprises a shaft having aproximal end and a distal end, an expansible member, a chemical and/orbiological sealing member, and a chemical and/or biological region orrelease region. The shaft is configured to advance through the tissuetract while the expansible member disposed on the distal end of theshaft is deployable within the blood vessel. The chemical and/orbiological sealing member is slidably disposed over the shaft andproximal the expansible member. The chemical and/or biological region orrelease region is disposed under the sealing member. Advantageously,displacement of the chemical and/or biological sealing member in aproximal direction exposes the region so as to allow for safe andcontrolled release of chemical and/or biological agents into the tissuetract for enhanced and complete hemostasis of the puncture site.

The chemical and/or biological sealing member prevents severecomplications as a result of chemical and/or biological agents fromcoming in contact with the blood stream by only allowing for thecontrolled exposure of such agents in the tissue tract. The sealingmember has a length in a range from about 0.1 cm to about 100 cm,typically from about 5 cm to about 20 cm and a diameter in a range fromabout 0.5 mm to about 5 mm, typically from about 1 mm to about 3 mm. Thesealing member may be a tubular member formed from a variety of medicalgrade materials, including coiled stainless steel tubing or polymermaterials such as nylon, polyurethane, polyimide, PEEL®, PEBAX®, and thelike.

In a preferred embodiment of the device, a tensioning element, such as aspring or coil, is further provided. The tensioning element is slidablydisposed over the shaft and under the sealing member proximal theexpansible member. Generally, during application of the device, thetensioning element is preferably positionable in the tissue tract, butin other instances may be outside the tissue tract. The tensioningelement gauges how much tension is being applied to the expansiblemember as it is seated against the puncture site so as to prevent a userfrom applying excessive force on the device causing undesirable movement(e.g., device is pulled out of patient body). The tensioning elementalso provides device compliance in cases of patient movement while thedevice is in place. The expansible member allows for sealing of thepuncture site while the tensioning element along with an external clipapply and maintain tension to the expansible occluder so that it isseated against the puncture site at a vascular surface (e.g., bloodvessel wall).

Positioning the expansible member against the vessel wall positions thechemical and/or biological region or release region outside the vessellumen at a predetermined distance from the vessel wall and proximal theexpansible member. Therefore, the expansible member provides not onlyocclusion at the vessel puncture site but also functions as a locator soas to position the chemical and/or biological region or release regionoutside the vessel lumen. This in turn ensures safe release of chemicaland/or biological agents in the tissue tract and outside the bloodstream. The predetermined distance is in a range from about 0 to about20 mm, typically in a range from about 2 mm to about 10 mm.

The chemical and/or biological region or release region has a length ina range from about 1 mm to about 100 mm, typically in a range from about5 mm to about 70 mm. It will be appreciated that the length and/orvolume of the region may be varied in order to integrate and releaseand/or expose the desired amount of chemical and/or biological agent. Inone embodiment, the chemical and/or biological region includes at leastone chemical and/or biological agent disposed on the distal end of theshaft proximal the expansible member and distal the tensioning element.In another embodiment, the region includes at least one chemical and/orbiological agent disposed on the tensioning element. The agents may becoated, sprayed, molded, dipped, vapor deposited, plasma deposited, orpainted thereon. Such a chemical and/or biological region on theocclusion device itself further minimizes variations due to usertechniques, which may be particularly problematic with injectionprotocols where such agents are injected into the tract by the user. Inyet another embodiment, the device may further incorporate an expansiblefeature disposed on the distal end of the shaft proximal the expansiblemember, wherein the region includes at least one chemical and/orbiological agent associated with the expansible feature.

In alternative embodiments of the present invention, the device mayfurther incorporate at least one chemical and/or biological deliveryconduit disposed over the shaft and under the tensioning element and achemical and/or biological injection port in fluid communication withthe delivery conduit. The injection port may be connected to a syringeby use of a compression fitting or with an integrated luer lock. Thechemical and/or biological agents are injected into the device via thesyringe once the device is properly positioned. It will be appreciatedthat the size of the injection port and the delivery conduit may beselected to control the delivery rate of such agents. In one example,the release region includes at least one opening, aperture, or orificein fluid communication with a distal end of the conduit proximal theexpansible member. It will be appreciated that any number, size, and/orshape of opening(s) may be utilized in order to obtain the desiredrelease rate of chemical and/or biological agent. The release region mayincorporate about 1 opening to about 100 openings, typically about 1opening to about 10 openings. In another example, the release regionincludes at least one porous member in fluid communication with a distalend of the conduit proximal the expansible member so as to allow for thedesired release of the chemical and/or biological agent.

A controlled delivery rate allows the chemical and/or biological agentsto “ooze” out of the release region. This may eliminate the potential ofhigh pressure release, which in turn minimizes the possibility of theseagents from entering the blood stream. In addition, the sealing memberserves to cover the chemical and/or biological release region so as toprevent any blood from flowing back through the release region, throughthe delivery conduit, and out through the injection port. The sealingmember is only slidably displaced, revealing the chemical and/orbiological release region, when it is desirable to deliver the chemicaland/or biological agents.

The device of the present invention may further incorporate a spacerelement disposed between the sealing member and the tensioning elementso that the sealing member may easily slide over the tensioning element.The spacer element may be a tubular member formed from a variety ofmaterials, including tubular polymer materials such as nylon,polyurethane, polyimide, PEEK®, PEBAX®, and the like. The device furtherincludes a handle on a proximal end of the shaft. A safety tab may bedisposed between the handle and the sealing member. The safety tabprevents any undesirable displacement of the sealing member so as toinhibit inadvertent release of chemical and/or biological agents.

The present invention integrates the expansible member, chemical and/orbiological sealing member, chemical and/or biological region or releaseregion, and tensioning element in a single unitary catheterconstruction. This simple construction and user interface allows forsafe, easy and convenient application of the device without numerousintermediary steps. The sealing member in combination with the locatingexpansible member ensures that the chemical and/or biological region orrelease region is only exposed in the tissue tract. This results in amore reliable, safe, and effective device which provides immediate andcomplete hemostasis, which in turn reduces the risk of bleeding,hematoma formation, thrombosis, embolization, and/or infection.

In another aspect of the present invention, methods for hemostasis of apuncture site in a blood vessel at a distal end of a tissue tract areprovided. One method comprises introducing any one of the closuredevices as described herein through the tissue tract. The expansiblemember is deployed at a distal end of the device within the bloodvessel. The chemical and/or biological sealing member disposed proximalthe expansible member is then displaced once properly positioned so asto expose a chemical and/or biological region or release region of thedevice. At least one chemical and/or biological agent is then releasedfrom and/or exposed on the device and into the tissue tract.

The sealing member is displaced in a proximal direction so as to exposeat least a portion of the region. This displacement distance is in arange from about 0.1 cm to about 10 cm, typically from about 0.5 cm toabout 7 cm. The method further comprises deploying the tensioningelement disposed proximal the expansible member within the tissue tractso that the expansible member is seated against a puncture site.Typically, deploying the tensioning element and displacing the sealingmember is carried out simultaneously so as to provide for easy andconvenient application of the device without numerous intermediarysteps. However, it will be appreciated that deployment of the tensioningelement may be carried out independently, typically prior todisplacement of the sealing member, so as to provide for properpositioning of the region or release region within the tissue tract andclosure of the puncture site.

The amount of tension applied to the expansible member by the tensioningcoil or spring is in the range from about 0.5 ounce to 30 ounces,typically in a range from about 2 ounces to 10 ounces. As describedabove, the expansible member locates and closes the puncture site in theblood vessel wall. Coil elongation is sufficient to provide adequateamount of tension on the expansible member to temporary seal thepuncture and to adequately displace the sealing member to reveal thechemical and/or biological region or release region. In someembodiments, coil elongation may be limited by a coupling member.Generally the amount of elongation of the tensioning coil may be thesame as for displacement of the sealing member. The tension provided bythe tensioning coil and the exposure of the chemical and/or biologicalagents may be maintained by application of an external clip on thetensioning coil, generally over the sealing member, wherein the cliprests over the skin at the puncture site.

Chemical and/or biological agent release generally comprises positioningthe region at a predetermined distance proximal to the expansible memberand outside the blood vessel wall. In particular, increasing the tensionin the coil positions the expansible member against the puncture siteand locates the chemical and/or biological region or release region inthe tissue tract at the predetermined distance. Further increase intension will cause the sealing member to disengage from an attachmentpoint at the proximal end of the expansible member and the tensioningcoil to elongate. Elongation of the tensioning coil will result in thesealing member to slide proximally so as to expose the region to thesurrounding tissue for release of the chemical and/or biological agent.

The chemical and/or biological agents may accelerate the coagulationprocess and promote the formation of coagulum at the puncture site so toachieve complete hemostasis. The chemical and/or biological agent maycomprise a variety of agents including clot promoting agents (e.g.,thrombin, fibrinogen, etc.) or vaso-constricting agents (e.g.,epinephrine, etc.). The chemical and/or biological agent is releasedand/or exposed at least about 0.1 minute, typically from about 0.5minute to about 4 hours, usually for the entire time that the occlusiondevice remains deployed. As described above, the occlusion device may bemodified in several ways (e.g., region length, region volume, releaseregion openings, conduit dimensions, number of conduits, or portdimensions) to achieve the desired chemical and/or biological agentrelease or exposure characteristics (e.g., rate, amount, time, etc.).The methods of the present invention may involve re-hydrating thechemical and/or biological agent with fluid in the tissue tract so as togenerate coagulum. These agents may use the blood components to form acoagulum even at the presence of anti-coagulants.

As described above, the chemical and/or biological agent may be coated,sprayed, molded, painted, dipped, or deposited at the region.Alternatively, chemical and/or biological agents may be injected in adelivery conduit in fluid communication with at least one openingdisposed at the release region. The sealing member in such an embodimentfurther prevents any blood from flowing back through the openings of therelease or exposure region prior to placing the expansible memberagainst the vessel wall when the release region is in the vessel lumen.Injection of chemical and/or biological agents in the presence of bloodin the chemical and/or biological delivery pathway may cause undesirablecoagulum to form in the pathway which could prevent the chemical and/orbiological agents from reaching the target site.

A further understanding of the nature and advantages of the presentinvention will become apparent by reference to the remaining portions ofthe specification and drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings should be read with reference to the detaileddescription. Like numbers in different drawings refer to like elements.The drawings, which are not necessarily to scale, illustratively depictembodiments of the present invention and are not intended to limit thescope of the invention.

FIGS. 1A and 1B illustrate a first embodiment of a drug eluting,self-tensioning vascular closure device for hemostasis of vascularpuncture sites constructed in accordance with the principles of thepresent invention.

FIGS. 2A and 2B illustrate an exploded view of the chemical and/orbiological region on the distal end of the device of FIGS. 1A and 1B.

FIGS. 3A and 3B illustrate the device of FIGS. 1A and 1B in an expandedconfiguration with the occluding member deployed.

FIGS. 4A and 4B illustrate the device of FIGS. 1A and 1B in an expandedconfiguration with the occluding member under tension after removal ofthe safety seal and with the chemical and/or biological sealing memberdisplaced proximally so as to expose the contents of the chemical and/orbiological region.

FIGS. 5A through 5F illustrate a method for hemostasis of a puncturesite in a body lumen employing the device of FIGS. 1A and 1B.

FIG. 6 illustrates a second embodiment of a drug eluting,self-tensioning vascular closure device for hemostasis of vascularpuncture sites constructed in accordance with the principles of thepresent invention.

FIG. 7 illustrates an exploded view of the chemical and/or biologicalinjection port and delivery conduit of the device of FIG. 6.

FIG. 8 illustrates an exploded view of the chemical and/or biologicalrelease region on the distal end of the device of FIG. 6.

FIG. 9 illustrates the device of FIG. 6 in an expanded configurationwith the occluding member deployed.

FIG. 10 illustrates the device of FIG. 6 in an expanded configurationwith the occluding member under tension and with the chemical and/orbiological sealing member displaced proximally so as to expose thechemical and/or biological release region so that attachment of asyringe to the chemical and/or biological injection port providesdelivery of chemical and/or biological agents.

DETAILED DESCRIPTION OF THE INVENTION

Referring now to FIGS. 1A and 1B, a first embodiment of a drug eluting,self-tensioning vascular occlusion device 70 for hemostasis of vascularpuncture sites is illustrated, wherein at least one chemical and/orbiological agent 152 is integrated with the device, typically beingimmobilized in or over a region, chamber, or absorptive reservoir 151(referred to collectively as a chemical and/or biological region).Device 70 generally comprises a first flexible elongated tubular member71 formed from coiled stainless steel tubing or polymer materials suchas nylon, polyurethane, polyimide, PEEL®, PEBAX®, and the like. Tubularmember 71 may have a length in a range from about 5 cm to about 50 cm,typically in the range from about 10 cm to about 30 cm and a diameter inthe range from about 0.25 mm to about 5 mm, typically in the range fromabout 0.5 mm to about 2 mm. An expansible occlusion member 74 isdisposed on the distal end of tubular member 71. A chemical and/orbiological sealing member 153 is slidably disposed over the tubularmember 71 and proximal the expansible member 74. The chemical and/orbiological region 151 containing the chemical and/or biological agent152 is typically disposed on the tubular member 71 (and/or optionallyover a tension coil as illustrated in device 90 in FIG. 1B) under thesealing member 153. Device 70 (FIG. 1A) and device 90 (FIG. 1B) differonly in the location of the chemical and/or biological agent. It will beappreciated that the above depictions are for illustrative purposes onlyand do not necessarily reflect the actual shape, size, or dimensions ofthe device 70. This applies to all depictions hereinafter.

The expansible member 74 may be formed from a variety of medical gradematerials, including stainless steel, superelastic material such asNITINOL®, or polymer materials such as nylon, polyurethane, polyimide,PEEL®, PEBAX®, and the like. Preferably the expansible member 74 is madeof superelastic NITINOL® material. The expansible member 74 in aretracted or collapsed state has a diameter of less than about 3 mm,preferably less than about 1.5 mm, as shown in FIGS. 1A and 1B, andFIGS. 2A and 2B. When deployed, the expansible member 74 in an expandedstate has a diameter in a range from about 3 mm to about 20 mm,preferably from about 3.5 mm to about 8 mm, as shown in FIGS. 3A/B and4A/B. Exemplary expansible structures 74 are described in detail inco-pending U.S. patent application Ser. No. 10/718,504. Still furtherembodiments of a braided mesh member 74 are described in U.S. Pat. No.5,836,913.

The expansible member 74 may at least partially or preferably be fullycovered with an elastomeric membrane material 96. Membrane 96 may beformed from a variety of medical grade materials, such as thermoplasticelastomers (e.g., CHRONOPRENE® or POLYBLEND®) having durometers in arange from 15 A to about 40 A. Membrane 96 may be connected at a distalconnection point 77 and a proximal connection point 75. Adhesives suchas LOCTITET® 4014 may be used to attach membrane 96 to the expansiblemember 74 and catheter shaft 71. Alternatively, membrane 96 may take aform of a sock having its distal end sealed through a heat stake processor the like. In this case membrane 96 may not have to be attacheddistally. Membrane 96 preferably has a diameter that is sufficient tocover the expansible member 74. In some embodiments, membrane 96 may bedesigned and attached to facilitate expansible member deployment as wellas to reduce the amount of required elongation when the expansiblemember 74 is deployed. This may be achieved by molding the membrane 96so that its midpoint diameter, where deployed expansible member 74 hasits greatest diameter, is larger than its proximal and distal enddiameters (e.g., a spherical shape). Membrane 96 may also be formed likea tube with a larger diameter than needed (e.g., diameter of retractedexpansible member 74), and then stretched over expansible member 74 andattached. The stretch should be enough to reduce the diameter of themembrane 96 to that of the expansible member 74. In such a case, whenmember 74 is deployed, there is less elongation and stress experiencedby membrane 96. The membrane 96 may additionally form a membrane tip ata distal end of catheter 70 so as to provide a soft and blunt point forsafer percutaneous access.

Referring now to FIGS. 2A/B, the chemical and/or biological agents 152may be composed of clot promoting agents such as thrombin and fibrinogenand/or vaso-constrictors such as epinephrine. These agents 152 may takeon a form of a powder, paste that can be applied to the chemical and/orbiological chamber or region 151. Alternatively, such agents 152 may bemolded in a form of a cylindrical tube with a longitudinal central holethat can be slidably disposed over member 71 and positioned betweenfixed attachment members 75 and 150 in the assembly process. Thechemical and/or biological chamber/region 151 is located between theproximal end of member 75 and distal end of attachment member 150.Alternatively, or additionally, the chemical and/or biological agentsmay be immobilized on the tension coil 86 described below. The length ofregion 151 determines the amount of chemical and/or biological agents152 that can be integrated with the device, as well as the extent of theexposure of such agents to the tissue. It should also be noted that byincreasing the outside diameters of members 75 and 150, the volume ofchamber 151 can be increased and hence the volume of the chemical and/orbiological agents 152 incorporated with the device. However, it may bedesirable to allow for a predetermined volume of blood to enter the gapbetween the chemical and/or biological agent layer and the sealingmember 153. This allows exposure of the chemical and/or biologicalagents to the bodily fluids without exposing these agents to the body.The trapped blood can then be given sufficient amount of time tointeract with the agents to become preconditioned prior to exposure totissue tract. The volume of this trapped blood may be controlled byadjusting the gap between the chemical and/or biological layer and theinside diameter of the sealing member. The degree of preconditioning maybe controlled by selecting the amount of time between the insertion ofthe device in the sheath and exposure of the agent(s) to blood and whenthe tension is applied and the sealing member is proximally displaced.The gap fills quickly due to capillary pull and the arterial bloodpressure once the distal end of the sealing member 153 comes in contactwith blood.

The chemical and/or biological sealing member 153 generally comprises aflexible elongated tubular member. In the device 70 of FIG. 1A, thetubular member 153 may have a length that extends from attachment member75, and overlapping member 75, to grip member 85, partially or fullyoverlapping member 85. The inside diameter of member 153, at least atthe distal end, is similar to the outside diameter of member 75. Member153 is slidably positioned, at least partially, over member 75. Theinteraction of members 153 and 75 provide for a barrier so that bloodwill not come in contact with the chemical and/or biological agent priorto the intended time.

In the preferred embodiment of the present invention, a tensioningelement 86 is slidably disposed over the tubular member 71 and proximalthe expansible member 74. The tensioning coil 86 is attached to thetubular member 71 with attachment member 150. Member 150 may be in atubular form and made from stainless steel tubing or polymer materialssuch as nylon, polyurethane, polyimide, PEEL®, PEBAX®, and the like.Coil 86, attachment member 150 and tubular member 71 are connectedtogether by use of epoxy. The attachment point may be from 1 mm to 100mm proximal to the member 75, preferably in the range of 5 mm to 50 mm.The tensioning element 86 is described in more detail in co-pending U.S.patent application Ser. No. 10/974,008.

The function of chemical and/or biological seal 153 is to provide abarrier between the chemical and/or biological agents 152 and bodilyfluids such as blood, and only allow the exposure of such agents to thetissue when the device is in correct position and the operator choosesto do so. Exposure of the chemical and/or biological region 151 to thesurrounding tissue happens when the tensioning coil 86 is grabbed atgrip member 85 and is pulled proximally with respect to member 75 toapply tension to the deployed expansible member 74 at the puncture site.The proximal pull of grip member 85 causes the tensioning coil 86 toelongate. The seal member 153 is attached to the coil 86 and grip member85. Since member 153 is not stretchable, the elongation of coil 86results in disengagement of the distal end of member 153 from member 75.Seal 153 slides proximally over the chemical and/or biologicalchamber/region 151 and exposes the chemical and/or biological agents 152to the surrounding tissue. A spacer 154 provides adequate space betweencoil 86 and sealing member 153, so that member 153 can easily slide overcoil 86. It should be noted that coil 86 elongation happens as theresult of interference of the occluding expansible member 74 with thevessel wall at the puncture site. This in turn slides the sealing member153 proximally, exposing the chemical and/or biological agents 152 inthe tissue tract where it is needed.

It will be appreciated that chemical and/or biological seal 153 may beconstructed to function independently from the tensioning coil 86. Also,in some embodiments, such as those of FIGS. 1B, 2B, 3B and 4B, a lengthof coil 86, or the entire length of coil 86 may be coated with thechemical and/or biological agent 152. In such case, when coil spring 86is elongated to provide tension to the expansible member 74, thedeformation of the elongating coil spring 86 may result in breaking offof the agents 152 from the coil. This may result in faster re-hydrationof the chemical and/or biological agents 152 and consequentlyacceleration of the coagulation process in the tract. Coating of thecoil 86 is not limited to such brittle agents, however, and the agentsmay be sufficiently “flexible” so that they remain immobilized despitestretching of the coil. Still further, the chemical and/or biologicalchamber 151 of device 70 may include an expansible feature over whichthe chemical and/or biological agent 152 is dispensed (e.g., coated).When desirable, this expansible member which may take the form of aballoon or a braided mesh, can be expanded, resulting in the agents 152breaking off in the surrounding tissue, and hence accelerating thechemical and/or biological reaction.

The device 70 of the present invention may further incorporate a safetyseal 155 to prevent inadvertent release of chemical and/or biologicalagents 152 by preventing coil 86 from sliding over member 71. Safetyseal 155 may be made of different materials and be implemented indifferent fashions. One such implementation may take the form of heatshrinkable tubing. The tubing may be shrunk over member 71 to theproximal end of the coil 86 or preferably overlapping grip member 85. Toremove the safety seal with ease, seal 155 may have a tab 156 that maybe easily grabbed and pulled, tearing the safety seal 155 along thelength of member 71. Removal of the safety seal 155 would allow coil 86to freely slide over tubular member 71, exposing the chemical and/orbiological agents 152 to the surrounding tissue.

The chemical and/or biological agent 152 is sealed from coming incontact with the circulating blood and generally is released and/orexposed in the tissue tract in the fascia at the puncture site. Duringdevice application, the expansible member 74 will be positioned andanchored against the puncture site in the vessel lumen. In particular,the expansible member 74 allows for sealing of the puncture site andlocating the chemical and/or biological agents 152 appropriately in thetissue tract. The tensioning element 86 applies and maintains tension tothe expansible occluder 74 while the sealing member 153 simultaneouslyreveals the chemical and/or biological agents 152 to bring such agentsin contact with the surrounding tissue to accelerate the process ofhemostasis.

Referring now to FIGS. 3A and 4A, a proximal end of the device 70comprises deployment means 78. Deployment of the expansible member 74typically comprises pushing or pulling the two part handle assembly 78coupled to the expansible member 74. A proximal end of handle assembly78 comprises an actuating assembly 101 which is coupled to a push/pullmember 76. Proximal movement of assembly 101 relative to a grip handle102 deploys the expansible member 74. The grip handle 102 comprises atubular member 103 formed from suitable metal tubing (e.g., stainlesssteel) or polymer materials (e.g., polyurethane, polyimide, PEEL®,PEBAX®, and the like). Member 103 is coupled to the catheter shaft 71 bymeans of an expander element 104 so as to account for the difference inan outside diameter of catheter 71 and an inside diameter of member 103.Elements 71, 103, and 104 may be attached by the use of adhesives.Member 103 further includes a feature 105, such as an indentation from acrimping process when element 103 is formed from a stainless steel orother metallic hypotube. Indentation 105 provides interference toelement 106 of the actuating assembly 101.

Actuating assembly 101 further includes a tubular member 107 that isattached to the push/pull member 76 by a crimp process and/or adhesive.Member 107 provides added stiffness to the actuating mechanism 101 aswell as provides for a larger surface area that consequently allows forenhanced adhesion of elements 106, 108, and 109 to member 107. Theseelements may comprise individual, separate parts, preferably formed frompolymer materials such as polyurethane, polyimide, PEEL®, PEBAX®, andthe like. These elements may be optionally incorporated into element 107through an over molding process. Once the device 70 is deployed,interference of detent element 106 with indentation 105 securelymaintains the expansible member 74 in its deployed position as shown inFIGS. 3A/B and 4A/B. A proximal end of detent 106 may have a shallowangle in relation to the catheter shaft 71 so as to provide simplifieddeployment of the expansible member 74. A distal end of detent 106 maybe more perpendicular to the catheter shaft 71 so as to provide moreinterference to feature 105, thereby requiring greater force to undeploythe expansible member 74. The increased undeployment force is desirableto avoid inadvertent device collapse. Optionally, indentation 105 may bedesigned so that a distal side of the feature has a much shallower anglein relation to the catheter shaft 71 than a proximal side.

Elements 108 and 109 primarily provide support and alignment of theactuating assembly 101. Element 109 may be formed from a bright distinctcolor to indicate when the expansible member 74 is deployed. Element 110comprises a tubular member, preferably having the same outer diameter asmember 103. A distal end of tubular member 110 abuts a proximal end ofmember 103 so as to provide a positive stop to the movement of theactuating assembly 101 during the undeployment of the expansible member74. Cap 111 at the most proximal end of the device 70 provides a softtip for easier undeployment of expansible member 74. Cap 111 may beformed from rubber or similar materials.

In operation, handle assembly 78 is held by grabbing onto element 103with one hand and element 110 with the other hand. Element 110 is thenpulled in a proximal direction while holding element 103 stationary. Aselement 110 is pulled back, detent 106 slides over indentation 105 untilit is completely moved to the proximal side of feature 105. FIGS. 3A/Band 4A/B illustrate the expansible member 74 that is in the form of atubular braided mesh in the deployed and expanded state. Theinterference between elements 105 and 106 keeps the expansible member 74in the deployed configuration. Undeployment of the device 70 may beeffected with a single hand. In particular, member 103 may be grabbed bythe palm of the hand while the thumb presses on cap 111. This causes theactuating mechanism 101 to move forward and the detent member 106 toslide distally over feature 105 resulting in the retraction of theexpansible member 74.

Referring now to FIGS. 5A through 5F, a method for hemostasis of apuncture site in a body lumen employing the device 70 of FIGS. 1A/B isillustrated. FIG. 5A depicts an existing introducer sheath 40 advancedthrough an opening in a skin surface 46, tissue tract in fascia 45 andvessel wall 43 and seated in a vessel lumen 41 at the completion of acatheterization procedure. Device 70 is then inserted through the hub ofthe sheath 40 and is advanced until the expansible member 74 is outsidethe sheath 40 and in the vessel lumen 41, as shown in FIG. 5B. Thispositioning may be indicated by a mark or feature on the catheter 71 orthe handle assembly 78.

As shown in FIG. 5C, the expansible member 74 is then deployed byoperation of the handle assembly 78. The sheath 40 is then slowly pulledout of the body, placing the expansible member 74 against the inner wallof the vessel 43 at the puncture site 42. As the sheath 40 is removed,the grip member 85 which is slidably disposed over the catheter shaft 71and the handle assembly 78 are revealed. Sheath 40 is then discarded,leaving deployed expansible member 74 seated at the puncture site 42 andthe chemical and/or biological chamber/region 151 in the tissue tract 47as shown in FIG. 5D. If the device is equipped with the safety seal 155as in device 70, then the safety seal 155 is removed by pulling the tab156 proximally along the catheter shaft.

Referring now to FIG. 5E, once safety seal 155 is removed, the gripelement 85 is grabbed and pulled in a proximal direction. Grip 85 ismoved proximally to provide adequate amount of tension to the deployedexpansible member 74 to achieve hemostasis. Typically, the amount oftension applied to the expansible member 74 is in the range of 0.5ounces to 30 ounces. In particular, proximal movement of grip 85 causessimultaneous elongation of the tensioning coil 86, causing theexpansible member to locate and close the puncture site 42, anddisplacement of the chemical and/or biological seal 153, exposing thechemical and/or biological agent 152 to the surrounding tissue at apredetermined distance from the puncture site. The elongated position ofcoil 86 is maintained by application of a small external clip 50 to thecatheter and seated against the surface of the skin 46, as shown in FIG.5E. Device 70 is left in this position for a period of time to achievethe desired promotion of hemostasis, for example to allow the chemicaland/or biological agent 152 to reconstitute with the fluids in thetissue tract 47, generating coagulum, or to allow contact activation,electrostatic interaction, or the like. Clip 50 is then removed and theexpansible member 74 is collapsed by manipulation of the handle assembly78. Device 70 is then removed, leaving the active chemical and/orbiological agents 152 and the coagulum in the tract 47 and adjacent thevessel puncture site 42, as shown in FIG. 5F. Additional finger pressureat the puncture site may be required to allow the coagulum to seal thesmall hole left in the vessel wall after removal of the device.

Referring now to FIG. 6, another embodiment of an exemplary drugeluting, self-tensioning vascular occlusion device 80 for hemostasis ofvascular puncture sites is illustrated, wherein the bio-active agents152 may be stored separately and safely injected into the target sitethrough a chemical and/or biological release region 163 once the deviceis properly positioned. The chemical and/or biological delivery systemof device 80 is composed of an elongated tubular member 160. Member 160may be coaxially located over member 71 as shown in FIG. 6. 160 has aninside diameter that is larger than the outside diameter of member 71.Member 160 is formed from coiled stainless steel tubing or polymermaterials such as nylon, polyurethane, polyimide, PEEK®, PEBAX®, and thelike. The gap made between the inside of member 160 and the outside ofmember 71 defines the chemical and/or biological delivery conduit 161.

Referring now to FIG. 8, the distal end of member 160 has a plurality ofopenings 162 defining the chemical and/or biological release region 163.Openings 162 vary in number and may be from 1 opening to 100 opening,preferably from 1 opening to 10 openings. The size, shape, and/or numberof openings 162 determines the rate of the release of the chemicaland/or biological agents into the surrounding tissues. Alternatively,the chemical and/or biological release region 163 may not be part ofmember 160, and may be a separate member, made of porous material whichis in fluid communication with member 160. In either embodiment, releaseregion 163 is located at a predetermined distance proximal to theexpansible member 74.

Referring now to FIG. 7, a chemical and/or biological injection port 164is illustrated. Port 164 comprises a flexible elongated tubular memberthat transitions to member 160 at its distal end by means of a couplingmember 165. At a proximal end, the port 164 provides a coupling to asyringe 167 for the injection of chemical and/or biological agents 152.Members 164 and 165 may be constructed from stainless steel tubing orpolymer materials such as nylon, polyurethane, polyimide, PEEL®, PEBAX®,and the like. Member 165 may or may not be a flexible member. Member 165preferably has an outside diameter that is not larger than the outsidediameter of the handle assembly 78. This ensures that device 80 can gothrough the existing sheath 40 without interference, as was describedfor device 70 in FIGS. 5A through 5F. Coupling member 165 is connectedto member 160 via member 166. Members 164, 165 and 160 are attached bymeans of epoxy to provide a fluid tight seal at attachment points 166.

It will be appreciated that the drug delivery conduit 160 may comprise asingle or multiple elongated tubular member(s) of varying length(s) thatrun(s) along the length of member 71. At a proximal end, these conduitscouple into delivery port 164 via coupling member 165. At a distal end,these tubular members may terminate at different points proximal to theexpansible member 74, dispersed over release region 163. Distally, theseconduits may have at least one opening for the release of the chemicaland/or biological agents into the region.

The chemical and/or biological sealing member 153 of device 80 functionsin a similar fashion as in device 70. In addition, the sealing member153 of device 80 prevents blood from flowing back through the chemicaland/or biological deliver path 163, 162, 161, 164. However, it will beappreciated that the back flow of blood through the chemical and/orbiological delivery pathway may be used as an indicator that thechemical and/or biological release region 163 is in the vessel lumen.When the back flow stops, that may be an indication that the releaseregion 163 is in the tissue tract, where there is no appreciable bloodpressure. In addition to the expansible member 74, this feature may addmore certainty to the positioning of the chemical and/or biologicalrelease region 163 and hence improve safety. In such case, prior toinjection of the chemical and/or biological agents 152, the pathway maybe flushed with solutions such as saline.

The tensioning coil 86, spacer element 154, and grip member 85 of device80 function in a similar fashion as in device 70. In device 80, however,the elongation of tensioning coil 86 is limited by the distal end ofcoupling member 165 at attachment point 166. The distance between theproximal end of the coil spring 86 and the distal end of coupling member165 at point 166 is long enough to provide the adequate amount oftension. This distance is also sufficient to allow the chemical and/orbiological seal 153 to move proximally to expose the entire chemicaland/or biological release region 163. FIG. 9 illustrates device 80 witha deployed expansible member 74. FIG. 10 illustrates device 80 when thecoil 86 is elongated to apply adequate amount of tension to expansiblemember 74 and to expose the chemical and/or biological release region163. The attachment of syringe 167 to delivery port 164 for delivery ofchemical and/or biological agents 152 to the target site is alsoillustrated.

In operation, device 80 is inserted through the sheath 40 and advanceduntil the expansible member 74 is out of the sheath 40 and in the bloodvessel 41. The expansible member 74 is deployed by manipulation of thehandle assembly 78, the sheath 40 is removed and discarded, and thedeployed expansible member 74 is placed against the inside wall of thevessel at the puncture site 42. Tension is then applied by proximallysliding grip member 85 of coil 86. The applied tension at the deployedexpansible member 74 will provide hemostasis, and locates chemicaland/or biological release region 163. Elongation of the coil 86 revealsthe chemical and/or biological release region 163 to the surroundingtissue tract 47. The tension and coil elongation are maintained byapplication of an external clip 50. Syringe 167 containing the chemicaland/or biological agents 152 is then connected to the chemical and/orbiological injection port 164. An adequate amount of the agent(s) isinjected into the site at tissue tract 47. The chemical and/orbiological agents 152 promote and accelerate the hemostatic process.After injection of the chemical and/or biological agents 152, enoughtime is given for the agents to react with the blood tissue to formcoagulum. External clip 50 is then removed, expansible member 74 iscollapsed, and device 80 is removed. Removal of the device 80 may befollowed by a few minutes of manual compression at the site to close thesmall hole left in the vessel wall.

Although certain exemplary embodiments and methods have been describedin some detail, for clarity of understanding and by way of example, itwill be apparent from the foregoing disclosure to those skilled in theart that variations, modifications, changes, and adaptations of suchembodiments and methods may be made without departing from the truespirit and scope of the invention. Therefore, the above descriptionshould not be taken as limiting the scope of the invention which isdefined by the appended claims.

1. A method for closing a blood vessel puncture site disposed at adistal end of a tissue tract, the method comprising: introducing aclosure device through the tissue tract; deploying an expansible memberof a distal end of the device within the blood vessel; exposing blood inthe tissue tract to a chemical and/or biological agent carried by thedevice, wherein said chemical and/or biological agent promoteshemostasis in the tissue tract; and collapsing the expansible member andremoving the device from the tissue tract.
 2. A method as in claim 1,wherein exposing comprises displacing a sealing member to expose achemical and/or biological agent which is immobilized on the closuredevice.
 3. A method as in claim 2, wherein the chemical and/orbiological agent is soluble in blood so that at least a portion thereofis released into the blood.
 4. A method as in claim 3, wherein thesoluble chemical and/or biological agent is selected from the groupconsisting of thrombin, epinephrine, and soluble chitosan.
 5. A methodas in claim 2, wherein the chemical and/or biological agent is insolubleand remaining immobilized on the device after exposure to blood.
 6. Amethod as in claim 5, wherein the insoluble chemical and/or biologicalagent has a negative electrical charge which promotes coagulation.
 7. Amethod as in claim 6, wherein the negatively charged chemical and/orbiological agent is selected from the group consisting of kaolin andsilica.
 8. A method as in claim 5, wherein the insoluble chemical and/orbiological agent has a positive electrical charge which attractsplatelets.
 9. A method as in claim 8, wherein the insoluble chemicaland/or biological agent comprises chitosan.
 10. A method as in claim 3,wherein the soluble chemical and/or biological agent inhibits theactivity of heparin.
 11. A method as in claim 10, wherein the solublechemical and/or biological agent comprises protamine sulfate.
 12. Amethod as in claim 1, wherein the chemical and/or biological agent isimmobilized within a region extending from 0.1 cm to 10 cm proximally ofthe expansible member.
 13. A method as in claim 12, wherein the sealingmember is displaced a distance in a range from about 0.1 cm, to about 10cm to expose the chemical and/or biological agent.
 14. A method as inclaim 1, wherein exposing comprises injecting the chemical and/orbiological agent through at least one delivery conduit in the device.15. A method as in claim 14, wherein the injected chemical and/orbiological agent is selected from thrombin, epinephrine, protaminesulfate, and suspensions of kaolin or chitosan.
 16. A method as in claim1, further comprising deploying a tensioning element disposed proximalthe expansible member so that the expansible member is seated against apuncture site.
 17. A method as in claim 16 wherein deploying thetensioning element and displacing the sealing member is carried outsimultaneously or sequentially.
 18. A method as in claim 16, furthercomprising limiting elongation of the tensioning element.
 19. A methodas in claim 1, wherein the chemical and/or biological agent is exposedfor a time period of at least about 0.1 minute.
 20. A device for closinga blood vessel puncture site disposed at a distal end of a tissue tract,the device comprising: a shaft having a proximal end and a distal end,the shaft being configured to be advanced through the tissue tract; anexpansible member disposed on the distal end of the shaft beingdeployable within the blood, vessel to occlude the blood vesselpuncture; a sealing member retractably disposed over at least a portionof the shaft proximal to the expansible member; and a chemical and/orbiological agent selected to promote, hemostasis disposed in a regionunder the sealing member, wherein at least a portion of the agent isexposed by retraction of the sealing member.
 21. A device as in claim20, further comprising a tensioning element slidably disposed over theshaft and under the sealing-member proximal the expansible member,wherein the tensioning element seats the expansible member against ablood vessel side of the puncture site.
 22. A device as in claim 20,wherein the region is positionable at a predetermined distance proximalto the expansible member and blood vessel wall.
 23. A device as in claim22, wherein at least one chemical and/or biological agent is disposed onthe distal end of the shaft proximal the expansible member.
 24. A deviceas in claim 22, wherein at least one, chemical and/or biological agentdisposed on the tensioning element.
 25. A device as in claim 22, furthercomprising at least one delivery conduit disposed over the shaft andunder the tensioning element configured to deliver a chemical and/orbiological agent proximal the expansible member.
 26. A device as inclaim 25, further comprising at least one porous member in fluidcommunication with a distal end of at least one delivery conduitproximal the expansible member.
 27. A device as in claim 21, furthercomprising a spacer element disposed between the sealing member and thetensioning element.
 28. A device as in claim 20, wherein a scalingmember is configured to be axially retracted to expose a chemical and/orbiological agent which is immobilized on the closure device.
 29. Adevice as in claim 22, wherein the chemical and/or biological agent issoluble in blood so that at least a portion thereof is released into theblood.
 30. A device as in claim 22, wherein the soluble chemical and/orbiological agent is selected from the group consisting of thrombin,epinephrine, and soluble chitosan.
 31. A device as in claim 22, whereinthe chemical and/or biological agent is insoluble in blood and/or has anegative charge.
 32. A device as in claim 31, wherein the negativelycharged chemical and/or biological agent is selected from the groupconsisting of kaolin and silica.
 33. A device as in claim 31, whereinthe insoluble chemical and/or biological agent has a positive electricalcharge which attracts platelets.
 34. A device as in claim 33, whereinthe insoluble chemical and/or biological agent comprises chitosan.
 35. Adevice as in claim 29, wherein the soluble chemical and/or biologicalagent inhibits the activity of heparin.
 36. A device as in claim 35,wherein the chemical and/or biological agent comprises protaminesulfate.
 37. A device as in claim 20, wherein the a region extends from0.1 cm to 10 cm.
 38. A method as in claim 2, wherein a predeterminedamount of blood may come in contact with chemical and/or biologicalagent for preconditioning prior to exposure to the tissue tract.
 39. Amethod as in claim 38, wherein the preconditioning may be from 0.1 to 15minutes.
 40. A method as in claim 38, wherein the amount of blood to bepreconditioned is determined by the gap between the sealing member andthe chemical and/or biological agent.
 41. A device as in claim 20,wherein a predetermined amount of blood may come in contact withchemical and/or biological agent for preconditioning prior to exposureto the tissue tract.
 42. A device as in claim 41, wherein thepreconditioning may be from 0.1 to 15 minutes.
 43. A device as in claim41, wherein the amount of blood to be preconditioned is determined bythe gap, between the sealing member and the region.